In silico and in vitro assessments of thio-linked pyrimidine-based compounds against Leishmania donovani
Résumé
Caused by Leishmania parasites, leishmaniases are a group of pathologies acknowledged by the World Health Organization as neglected tropical diseases. Current therapies for treating these infections count on a limited arsenal of drugs with several downsides that restrict their use, namely the development of drug resistance. Innovative medicines with improved efficacy, safety, and a lower tendence for resistance development are imperatively needed.1 Trypanothione reductase (TR) critical function in sustaining the parasite's redox machinery, converting the disulfide bond of trypanothione disulfide (TS2) into reduced trypanothione T(SH)2, makes it a promising biomolecular target in the search for novel antileishmanial compounds. This di-thiol is crucial for scavenging reactive species for Leishmania2,3, offering a potential avenue for drug development. Furthermore, TR offers several advantages, highlighting its structural resemblance to all Trypanosomatidae parasites and its absence in the mammalian host.4 In the search for improved antileishmanial options, a study discovered the potential of aryl sulfides in deactivating TR.3,5 Based on these findings, we unveil the synthesis of a library of novel thio-linked pyrimidine-based compounds applying the Buchwald–Hartwig reaction that leads to the formation of different products by changing the reaction time. Our findings from the computational studies show that all compounds interact with the residues from the NADPH-binding site, thus limiting the interaction between TR and its cofactor, NADPH. We also provide the results of all compounds' in vitro antileishmanial activity against L. donovani axenic and intramacrophage amastigotes, and their cytotoxicity against Raw 264.7 cells. Compounds IC69 and IC90 were the most effective against both forms of Leishmania, exhibiting IC50 values lower than the control, miltefosine (Figure 1).
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